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P10 - Mitochondria and
Lipotoxicity
Wolfgang Graier
Mitochondria, instigators and/or targets of lipotoxicity?
Besides their profound
importance in cellular energy metabolism, mitochondria serve as key
regulators for vital signaling pathways. Due to their central function
in the metabolism of all major nutrition constituents, mitochondria are
exposed to large amounts of substrates (FA, pyruvate), which when
present in excess cause a “substrate overload” that is thaught to be
causative for cell dysfunction in metabolic disorders, such as
hypertriglyceridemia and diabetes. Thus, these organelles are initial
targets in conditions of metabolic stress at the onset of
cardiovascular dysfunction. Although the contribution of mitochondria
to apoptosis under conditions of excessive substrate overflow is
reported, the mechanisms preceding this endpoint of lipo- and
glucotoxicity, mitochondrial adaptation and dysfunction, and their
consequences for cellular signal transduction have not been elucidated
in detail so far.
Consequently, this project is designed to
investigate early signaling phenomena leading to changes in
mitochondrial functions upon substrate overload and cause
cellular/tissue dysfunction prior to the initiation of apoptosis. The
following aspects will be elaborated in the context of
substrate-induced lipotoxicity:
- Alterations
in the phosphorylation patterns of mitochondrial proteins by tyrosine
kinases as indicators of the organelle’s adaptation and dysfunction
upon substrate overload;
- Molecular
mechanisms of mitochondrial protection against excessive substrate
overflow by uncoupling protein 2 and 3 (UCP2/3);
- Contribution
of NAD(P)H oxidase and its associated plasma membrane H+ conductance
(GvH+) to mitochondrial and cell dysfunction under conditions of
substrate overload.
The significance of the mitochondrial
phosphoproteome for organelle/cell functions and dysfunction will be
addressed in uterine arteries and cultured vascular cells isolated from
control (healthy in terms of cardiovascular and metabolic disorders),
hypertriglyceridemic, and diabetic individuals. The involvement of
UCP2/3 and NAD(P)H oxidase/GvH+ will be assessed in cultured vascular
cells from human uterine artery. These issues will be further
investigated in suitable knockout mouse models (UCP2-/-, UCP3-/-,
gp91phox-/-) and their littermates generated by crossbreeding with two
established models that develop vascular dysfunction due to FA overload
and hypoinsulinemic diabetes (MCK-LPL and pdx1PB-HNF6).
A better understanding of the molecular mechanisms involved in the
onset of mitochondrial adaptation and dysfunction upon substrate
overload, will allow for therapeutic intervention in
lipotoxicity-induced cardiovascular dysfunction prior to severe
clinical manifestations.
Principal
hypothesis and objectives
Mitochondria, which
represent the intercept point in the metabolism of all major
nutritional constituents, are an initial target of overloading by
metabolic substrates (lipids, D-glucose) and, accordingly, instigate
development of vascular cell dysfunction under these conditions. We
propose to investigate alterations in mitochondrial protein
phosphorylation as molecular events responsible for mitochondrial and
cellular dysfunction in vascular cells and blood vessels. We intend to
examine the molecular mechanisms behind the capacity of uncoupling
proteins 2 and 3 (UCP2/3) to counteract mitochondrial and vascular cell
dysfunction under conditions of substrate overload. Moreover, we will
explore the mutual interplay of NAD(P)H oxidases and their associated
plasma membrane H+ conductance with mitochondria in the context of
substrate-induced lipotoxicity.
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Wolfgang Graier
CV
& Publication List W. Graier in pdf format
Affiliation
Medical University of
Graz
Institute of Molecular Biology
and Biochemistry
Center of Molecular Medicine
Harrachgasse 21, A-8010 Graz
Homepage
Wolfgang Graier
email: wolfgang.graier@meduni-graz.at
Other
Research Grants
Project Title
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Grant No.
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Spatial and organelle Ca2+ signaling: regulation,
function and dysfunction
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FWF
P16860-B9 |
| Testing new compounds against endothelial dysfunction |
Servier
Intl, F
since 2002
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| Design of improved application techniques of high resolution
(confocal)
fluorescence microscopy |
Zeiss,
A
since 2004
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